FDA Mulls Parameters for Allergy Therapies

Researching allergy treatments tough in young children and infants

Faced with rising rates of allergic conditions in children and a dearth of interventions available to stop them early in life, the FDA brought in a group of independent advisors to help it decide how to move forward in developing and approving immunotherapies for curing, not just managing these conditions.

With no specific products to review and no up-or-down voting questions, the agency's Allergenic Products Advisory Committee heard from FDA officials and academic experts, who discussed a range of issues clinical trial design, appropriate end points, age-unique testing issues, and safety and efficacy for novel products aimed at asthma prevention and treatment and food allergies.

The panel spent a lot of time discussing the unique and challenging safety issues involved with testing and treatment of young children and infants.

"I can't help worrying about traumatizing infants with immunotherapy," one of the panelists said.

"Common adverse events may be too difficult to reliably detect and treat [in young children]," said Suyoung Tina Chang, MD, of the FDA Division of Vaccines and Related Product Applications.

Panel members worried that young children -- an important population to try to treat -- would be unable to articulate when they are experiencing symptoms such as pruritus, mouth edema, and throat irritation before anaphylaxis becomes life-threatening anaphylaxis. And that a lack of reliable data on trials involving infants and children under 5 would make it difficult to know where to set parameters.

But six people, including an immunotherapy developer from Merck, stepped up to the microphone during the open public hearing and asked the FDA to do everything they can to get the ball rolling, especially for severe peanut allergies.

Food Allergies

A number of academic groups have tested "home-brew" peanut immunotherapies in children, with encouraging results, but there has been no clear path to a standardized treatment regimen that would safely produce reliable benefits. The situation is similar for egg and dairy allergies.

As a result, "there are no licensed immunotherapies for food allergies," Kathleen Hise, MD, of the Division of Vaccines and Related Product Applications, noted in the first presentation. "And the high rate of adverse events leads to 10% to 20% subject withdrawal, including anaphylaxis, asthma, and oropharyngeal edema. This is especially problematic in kids because they're unable to alert about early signs of reaction."

Hise suggested a potential alternative to food challenge with field trials that have a primary endpoint of reduction of rate or severity of reactions to accident.

Hise also suggested that biomarkers could serve as allergen specific surrogate endpoints, but during the discussion section, several of the panelists said they couldn't see a way around the food challenge, and better metrics for biomarkers would need to be developed for measure.

Additionally undefined metrics and quantifiable measures across many areas of allergy study have been problematic in drug development.

"To support labeling, agreement is needed between the applicant and the FDA on study design, study population, and clinical parameters, demonstrating desensitization, and sustained immunosuppressives and tolerance," Hise said.

"We need to address reproducibility of double-blind studies," said John M. Kelso, MD, of Scripps Clinic in San Diego. "There may be a number of variables that can go into what allows the patient to have a reaction to a food on any given day. So, how many distinct challenges do you have to do to prove efficacy?"

"Atopic March"

Thomas Platts-Mills, PhD, of the University of Virginia School of Medicine, discussed the phenomenon known as atopic march, which he described as "progression from one allergen or epitope to another or as progression of clinical disease."

But, he noted, "many or most patients do not proceed consistently, in some studies only 7% of allergic kids have consistent pattern."

The truly important thing to notice is that here in the first 3 years of life, there's a lot of eczema and wheezing, and most of this in the first 3 years of life is viral, Platts-Mills said. "There are no significantly elevated IgE levels, but atopic after age 3 becomes aggressive."

Platts-Mills presented data on the history of allergy development in Europe in the 19th century and in America in the early 20th century, suggesting a rise in hay fever rates could be tied to better household and personal hygiene impacting antibody development, a phenomenon that he then tied to allergy progression in today's developing countries across the globe. In Ghana, Costa Rica, and Ecuador increased allergy rates suggested changes in living conditions from diverse environmental exposure to more sterilized homes, water, and skin have lead to the development of allergies.

"All the FDA has to do is approve [an] immunotherapy for cockroach and asthma will be abolished in 5 years," he said.

According to Platts-Mills, diverse exposures work on the IgE B-cell mechanism, and there are different methods of producing an IgE response, such as dog fecal bacteria, probiotics, oral allergens, and abrading undamaged skin.

"Living on a farm is a potential intervention," he added. "Most children get washed too well by their mothers ... We have mothers who are washing babies twice a day with detergent. That's being abused with a lot of product. You are taking fat out of the skin the whole time."

Platts-Mills argued for having a dog in the home that is allowed to go run around outside. "A dog in the home can alter the microbiome of the infant in the first few months of life, increasing Lactobacilli in the stool. House dust exposure mediates gut microbiome Lactobacilli enrichment and airway immune defense against allergens and virus infection."

Platts-Mills also suggests that alum in certain vaccines could contribute to allergies.

Asthma Prevention

The FDA has identified challenges for evaluating the effectiveness of allergen immunotherapy for prevention of asthma, according to Chang, who gave the final presentation.

For infants and children under 5 years old, asthma is a heterogeneous disorder with variable expression influenced by many factors. The factors the FDA knows are good for inclusion criteria include family history of atopic progression: asthma, atopic dermatitis, food allergy, allergic rhinitis, and allergic sensitization.

But, Chang added, guidelines for asthma in adults don't work well for kids under 5. "Not all children who wheeze develop asthma, and they're too young to perform spirometry," Chang said. "Wheeze can be associated with several other things."

Chang said that additional, accurate diagnostic tools will be required to progress, as well as better defined length of follow-up for asthma prevention tools.

No votes were taken at the meeting; the FDA will use the day's discussion to develop guidance for manufacturers in designing the clinical trials needed to support marketing applications.

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